Pregnant mice treated with a synthetic antagonist of toll-like receptor 4 (TLR4A) had fetal death rates about half those in untreated animals, according to a report in the August issue of the Journal of Immunology.

The efficacy of TLR4A adds to the scarce arsenal in the prevention of [preterm birth], concluded Yiping W. Han, Ph.D., of Case Western Reserve University, here, and colleagues.

"TLR4A . . . did not exhibit any detectable adverse effect on either the fetus or the mother in our study. Thus, it is a promising anti-inflammatory agent for the treatment and prevention of adverse pregnancy outcomes," they said.

Preterm birth accounts for about 12% of all live births in the United States, 70% of perinatal mortality, and almost half of all long-term neurologic morbidity, the authors wrote. Intrauterine infection plays a role in many cases.

Fusobacterium nucleatum, a gram-negative anaerobe, is one of the organisms most often associated with preterm birth, the authors noted. It is detected in 10% to 30% of cases involving intact membranes and more than 80% of cases associated with ruptured membranes.

F. nucleatum activates TLR2 and TLR4, members of a family of pattern-recognition receptors that have pivotal roles in host inflammatory responses.

Dr. Han and colleagues found lower rates of fetal death in TLR4-deficient mice exposed to F. nucleatum (3.7% to 8%) compared with rates in animals that had intact TLR4 receptors (about 80%).

Moreover, they said, fetal death rates were not decreased in TLR2-deficient animals.

The investigators found that TLR4-deficient mice had no necroinflammatory response to the bacteria, leading to the hypothesis that inflammation, not infection per se, was the driving force in fetal death.

The researchers examined the effects of F. nucleatum exposure in three groups of mice: those with intact TLR4 receptors, TLR4-deficient mice, and a group with intact receptors treated with the TLR4 antagonist.

They found that TLR4-deficient mice gave birth to healthy pups.

In TLR4+ animals, the antagonist blocked the receptors' interaction with the bacteria, and few fetal deaths occurred.

In contrast, untreated TLR4+ animals had a 50% increase in the fetal death rate compared with the treated animals.

Their work also showed that the TLR4 antagonist had no effect on bacterial colonization, confirming the hypothesis that bacteria-induced inflammation leads to fetal death, the authors said.

"[B]ecause TLR4A is nonbactericidal, it probably will achieve a maximal protective effect as an adjunct to specific antimicrobial therapy," the authors concluded.

The authors disclosed no conflicts of interest. The study was supported by the Philip Morris External Research Program and the National Institutes of Health.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine